1009
cross-infection and cross-contamination of uninfected carcasses by infected birds. 15 Most human salmonella infections are localised to the alimentary tract. Although unpleasant and
THE LANCET Salmonellosis—an Unhappy Turn of Events last year there have been many reports in the United Kingdom of resistance to SINCE
early
chloramphenicol, typhimurium isolated
antimicrobial drugs, including
among strains of Salmonella from human beings and food animals.’-10 According to THRELFALL, WARD, and ROWE5 all strains of S. typhimurium of phage type 204, which is now the predominant type in human and bovine infections in the British Isles, are resistant to one or more antimicrobial drugs. From 1974 until 1977, the most common pattern was that of resistance to sulphonamides and tetracyclines. In June, 1977, however, a strain of phage type 204 which had gained an R factor (plasmid) coding for resistance to
chloramphenicol, streptomycin, sulphonamides,
and tetracycline (R-type CSSuT) was responsible for a small outbreak of salmonellosis on a farm in Leicestershire with an extensive calf-dealing trade. As a result of the widespread distribution of calves infected with this multiresistant strain, phage type 204 of R-type CSSuT has become established in calf herds in Britain and has been responsible for numerous outbreaks of salmonellosis. Human infection with this chloramphenicol-resistant strain first appeared in August, 1977, and many people have now been infected. A similar strain has been isolated also from pigs and from meat products for human consumption. Since 1967, S. typhimurium, the salmonella serotype largely responsible for infections in cattle, is no longer the serotype most often isolated from human beings in the U.K., having been replaced by others such as S. agona, S. enteritidis, S. heidelberg, S. virchow, and S. hadar, which are serotypes derived mainly from chickens and turkeys. 11-14 The principal reason is almost certainly a rise in the price of beef. Chicken and turkey are the cheapest and most popular forms of animal food protein in the U.K.; and modern methods of large-scale production and processing of poultry often lead to 1 Davies, G., Sojka,
W.
J., Wray, C., Williams, B.
M. Vet. Rec.
1978, 103,
67 2
Animal Dis. Rep. 1978, 2, no 2, p 4. no 3, p. 2
3 ibib 4
Threltall, E. J., Ward, L. R., Rowe, B. Br. med. J. 1978, ii, 997. Threlfall, E J, Ward, L R., Rowe, B. Vet. Rec. 1978, 103, 438.
6 ibid
1978, 103, 435.
temporarily disabling they are usually self-limiting and require no more than symptomatic treatment. Indeed, in most instances treatment with antimicrobial agents is not helpful and is likely to prolong carriage of the organism 16-something to be avoided, especially in food handlers and nurses. Occasionally, however, there arise serious systemic
life-threatening salmonella infections other than those caused by S. typhi (the causal organism of typhoid fever, which always originates from a human case or carrier). Such exceptional forms of salmonella infection, some of which result from cross-infection in hospital nurseries for newly born babies,l’ do require prompt and effective treatment with an antimicrobial agent. In these circumstances there is a choice of several drugs, but for older children and adults many infectious disease physicians and clinical microbiologists still see chloramphenicol as the drug of choice, as it is for typhoid fever. Since most salmonella infections in man are derived directly from meat or meat products made from food animals, human infections with chloramphenicol-resistant strains of S. typhimurium may sooner or later become widespread. Such a prospect alone is disturbing enough, but something even more perplexing is to be found in an article by RICHARDS and co-workers, who refer to the earlier report by THRELFALL et a1.4that strains of S. typhimurium of phage type 193 from both bovine and human sources contain resistance plasmids derived from the epidemic phage type 204 strain. Furthermore, some bovine isolations of type 193 have acquired plasmid-encoded resistance to trimethoprim, which suggests that drugs such as co-trimoxazole (which contains trimethoprim) are now being used in cattle. According to RICHARDS and co-workers, the evidence suggests that the gene(s) concerned with trimethoprim resistance may be carried by a transposon-a specific segment of D.N.A. with the ability to be transposed, or to "jump", from one plasmid to another or to other replicons such as bacterial chromosomes or bacteriophage genomes. By means of transposons, resistance genes may be disseminated widely among bacteria of many genera. Already another transposon that determines TEM penicillinase has spread throughout the world among plasmids of different incompatibility groups and bacteria of many genera, including Haemophilus influenzae18 and Neisseria gonorrhcee,’9 presumably as a ’result of
the very extensive worldwide
use
of
ampicillin.
7 Richards, H., Datta, N., Sojka, W. J., Wray, C. Lancet, 1978, ii, 1194.
8 9 10 11 12
13 14
Richardson, A. Vet Rec 1978, 103, 518. Appleyard, W. T., Clegg, F. G. ibid. 1978, 103, 542. Threlfall, E. J., Ward, L. R., Rowe, B. ibid. 1979, 104, 60. Vernon, E. Publ Hlth, Lond. 1969, 83, 205. Vernon, E. ibid 1970, 84, 239. Vernon, E., Tillett, H. E. ibid. 1974, 88, 225. Vernon, E. ibid. 1977, 91, 225.
15 McCoy, J. H. J. Hyg., Camb. 1975, 74, 271. 16. Geddes, A. M. Br. med. J. 1973, i, 100. 17. Baine, W. B., Gangarosa, E. J., Bennett, J. V., Barker, W. H. J. infect. Dis. 1973, 128, 357 18. Laufs, R., Kauflers, P.-M. J gen. Microbiol 1977, 103, 277. 19. Elwell, L. P., Roberts, M., Mayer, L. W., Falkow, S Antimicrob. Agents Chemother. 1977, 11, 528.
1010
Therefore, the identification of trimethoprim-resistransposons in salmonellas of bovine origin have serious implications. may It is now almost ten years since the Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine under the chairmanship of Prof. MICHAEL SWANN published their report. 20 The committee had strong views on the control of the use of antimicrobial agents in animal husbandry, whether as food additives or for treatment of infections in food animals. The committee advocated that antimicrobial agents used in the treatment of human animal infections should not be used as growth-promoting additives in animal feed. More specifically they recommended that the use of chloramphenicol and the prevalence of resistance to it should be monitored in human and veterinary medicine and prompt action should be taken if either increased significantly. As a result of the Swann Committee recommendations, antimicrobials which are important therapeutic agents in veterinary and human medicine are no longer to be used as growth promoters, and all new agents proposed as feed additives are scrutinised to ensure that their administration is unlikely to lead directly to resistance against antimicrobial agents used therapeutically. But the use of antimicrobial agents for treatment of infected farm animals is much harder to control. Furthermore, there is the possibility of genetic transfer to human and animal pathogens of resistance to antimicrobial agents permitted as food additives, being accompanied by resistance to antimicrobial agents used for treating people and animals. E. S. ANDERSON has repeatedly pointed out21,22 that when an organism has acquired resistance to several antimicrobial agents, and especially when the genes for these resistances are linked on one plasmid, exposure to any one of the agents will select for resistance to them all. The position today is unhappily reminiscent of that of the early 1960s, when epidemics of salmonellosis led to the appointment of the Swann Committee. Ten years after the committee’s report, resistant salmonellas in food animals are not even under control, much less eliminated. Is it sensible or even necessary to use chloramphenicol, and other agents which can save the lives of human beings, in the treatment of salmonellosis in calves and other food animals? To what extent are antibiotics, prescribed for treatment of infections in animals, being diverted, without veterinary consent, into use as feed additives for promoting growth?) Has everyone forgotten the lessons learned in previous outbreaks about the role of bad husbandry inl causing infection, and about how good rearing
tance
.
þ
_
-
Report of
21 22
bandry and Veterinary Medicine, H M Stationery Office, 1969. Anderson,E. S., Lewis M. J. Nature, 1965, 206, 579. Anderson, FS. New scientist, 1974 61, 750.
the
Joint Committee
on
the
use
of Antibiotics
Animal Hus
20
in
eliminate infection? And what has become of the proposed protein processing order,-, under which all protein-containing animal feed used in the U.K. would be subjected to heat-treatment sufficient to destroy salmonellas? This measure is long overdue. To be effective such an order would have to be accompanied by systematic eradication of salmonellas from existing stocks of animals and the premises in which they are housed. One final point. Those doctors who criticise their veterinary colleagues for the indiscriminate and inappropriate use of antimicrobial agents in animals, should pause awhile before casting their stones. We all need to think more critically before prescribing an antimicrobial agent, whether it be the latest mycin or an older but still valuable member of our antimicrobial reserve. A little more restraint in prescribing, and a few more controls in barn and field, could greatly lessen the rate at which our antimicrobial resources are being squandered.
practice
-
can
THE NEW GOVERNMENT
PERHAPS the new Conservative Government was elected because enough voters acted in the belief that only a change in leadership could realise Britain’s full economic potential and unite the people in a creative effort to dispel the total self-interest induced by inflation and fear of unemployment. Whatever the reasons, those who detected vagueness, inconsistency, and disruptiveness in Conservative arguments must now take heart from an air of hopefulness in the land-an emotion running counter to the woe cried by many who believe they have witnessed no more than another tilt in an impotent political seesaw. Despite fears that they were inviting the citizens to expect early and ample reward for votes, the Conservatives won a majority large enough to show that their case had indeed generated more hope than Mr Callaghan could evoke after the positive achievements of his administration had been shadowed by the winter’s troubles, but a majority small enough to counsel caution against swift action in sensitive matters like industrial relations and trade-union powers. The goodwill now on the surface (maybe the nation is elated by its own daring in choosing a woman as Prime Minister) must be deepened and sustained if reforms and changes of attitude are to be won by consultation and avoidance of conflict. For the National Health Service, with the report of the Royal Commission expected in a month or two, no sudden change is forecast. The N.H.S. sprang from an idealistic base which seemed secure in 1948 and yet has proved in the ’60s and ’70s to be terribly vulnerable to rising costs, the inflation-stoked demands of its employees, and the high expectations of a society which sees that medical care has much more to offer than it had in the ’40s. As the Conservative manifesto argued, more can be achieved for the same money by further improvements in N.H.S. housekeeping. But there is little to be gained and much to be lost by cutting the cost of the N.H.S. through new or higher financial barriers or bB encouraging private practice (at the inevitable expense of N.H.S. manpower resources). It is, in fact, the cen
cross-infection and cross-contamination of uninfected carcasses by infected birds. 15 Most human salmonella infections are localised to the alimentary tract. Although unpleasant and
THE LANCET Salmonellosis—an Unhappy Turn of Events last year there have been many reports in the United Kingdom of resistance to SINCE
early
chloramphenicol, typhimurium isolated
antimicrobial drugs, including
among strains of Salmonella from human beings and food animals.’-10 According to THRELFALL, WARD, and ROWE5 all strains of S. typhimurium of phage type 204, which is now the predominant type in human and bovine infections in the British Isles, are resistant to one or more antimicrobial drugs. From 1974 until 1977, the most common pattern was that of resistance to sulphonamides and tetracyclines. In June, 1977, however, a strain of phage type 204 which had gained an R factor (plasmid) coding for resistance to
chloramphenicol, streptomycin, sulphonamides,
and tetracycline (R-type CSSuT) was responsible for a small outbreak of salmonellosis on a farm in Leicestershire with an extensive calf-dealing trade. As a result of the widespread distribution of calves infected with this multiresistant strain, phage type 204 of R-type CSSuT has become established in calf herds in Britain and has been responsible for numerous outbreaks of salmonellosis. Human infection with this chloramphenicol-resistant strain first appeared in August, 1977, and many people have now been infected. A similar strain has been isolated also from pigs and from meat products for human consumption. Since 1967, S. typhimurium, the salmonella serotype largely responsible for infections in cattle, is no longer the serotype most often isolated from human beings in the U.K., having been replaced by others such as S. agona, S. enteritidis, S. heidelberg, S. virchow, and S. hadar, which are serotypes derived mainly from chickens and turkeys. 11-14 The principal reason is almost certainly a rise in the price of beef. Chicken and turkey are the cheapest and most popular forms of animal food protein in the U.K.; and modern methods of large-scale production and processing of poultry often lead to 1 Davies, G., Sojka,
W.
J., Wray, C., Williams, B.
M. Vet. Rec.
1978, 103,
67 2
Animal Dis. Rep. 1978, 2, no 2, p 4. no 3, p. 2
3 ibib 4
Threltall, E. J., Ward, L. R., Rowe, B. Br. med. J. 1978, ii, 997. Threlfall, E J, Ward, L R., Rowe, B. Vet. Rec. 1978, 103, 438.
6 ibid
1978, 103, 435.
temporarily disabling they are usually self-limiting and require no more than symptomatic treatment. Indeed, in most instances treatment with antimicrobial agents is not helpful and is likely to prolong carriage of the organism 16-something to be avoided, especially in food handlers and nurses. Occasionally, however, there arise serious systemic
life-threatening salmonella infections other than those caused by S. typhi (the causal organism of typhoid fever, which always originates from a human case or carrier). Such exceptional forms of salmonella infection, some of which result from cross-infection in hospital nurseries for newly born babies,l’ do require prompt and effective treatment with an antimicrobial agent. In these circumstances there is a choice of several drugs, but for older children and adults many infectious disease physicians and clinical microbiologists still see chloramphenicol as the drug of choice, as it is for typhoid fever. Since most salmonella infections in man are derived directly from meat or meat products made from food animals, human infections with chloramphenicol-resistant strains of S. typhimurium may sooner or later become widespread. Such a prospect alone is disturbing enough, but something even more perplexing is to be found in an article by RICHARDS and co-workers, who refer to the earlier report by THRELFALL et a1.4that strains of S. typhimurium of phage type 193 from both bovine and human sources contain resistance plasmids derived from the epidemic phage type 204 strain. Furthermore, some bovine isolations of type 193 have acquired plasmid-encoded resistance to trimethoprim, which suggests that drugs such as co-trimoxazole (which contains trimethoprim) are now being used in cattle. According to RICHARDS and co-workers, the evidence suggests that the gene(s) concerned with trimethoprim resistance may be carried by a transposon-a specific segment of D.N.A. with the ability to be transposed, or to "jump", from one plasmid to another or to other replicons such as bacterial chromosomes or bacteriophage genomes. By means of transposons, resistance genes may be disseminated widely among bacteria of many genera. Already another transposon that determines TEM penicillinase has spread throughout the world among plasmids of different incompatibility groups and bacteria of many genera, including Haemophilus influenzae18 and Neisseria gonorrhcee,’9 presumably as a ’result of
the very extensive worldwide
use
of
ampicillin.
7 Richards, H., Datta, N., Sojka, W. J., Wray, C. Lancet, 1978, ii, 1194.
8 9 10 11 12
13 14
Richardson, A. Vet Rec 1978, 103, 518. Appleyard, W. T., Clegg, F. G. ibid. 1978, 103, 542. Threlfall, E. J., Ward, L. R., Rowe, B. ibid. 1979, 104, 60. Vernon, E. Publ Hlth, Lond. 1969, 83, 205. Vernon, E. ibid 1970, 84, 239. Vernon, E., Tillett, H. E. ibid. 1974, 88, 225. Vernon, E. ibid. 1977, 91, 225.
15 McCoy, J. H. J. Hyg., Camb. 1975, 74, 271. 16. Geddes, A. M. Br. med. J. 1973, i, 100. 17. Baine, W. B., Gangarosa, E. J., Bennett, J. V., Barker, W. H. J. infect. Dis. 1973, 128, 357 18. Laufs, R., Kauflers, P.-M. J gen. Microbiol 1977, 103, 277. 19. Elwell, L. P., Roberts, M., Mayer, L. W., Falkow, S Antimicrob. Agents Chemother. 1977, 11, 528.
1010
Therefore, the identification of trimethoprim-resistransposons in salmonellas of bovine origin have serious implications. may It is now almost ten years since the Joint Committee on the Use of Antibiotics in Animal Husbandry and Veterinary Medicine under the chairmanship of Prof. MICHAEL SWANN published their report. 20 The committee had strong views on the control of the use of antimicrobial agents in animal husbandry, whether as food additives or for treatment of infections in food animals. The committee advocated that antimicrobial agents used in the treatment of human animal infections should not be used as growth-promoting additives in animal feed. More specifically they recommended that the use of chloramphenicol and the prevalence of resistance to it should be monitored in human and veterinary medicine and prompt action should be taken if either increased significantly. As a result of the Swann Committee recommendations, antimicrobials which are important therapeutic agents in veterinary and human medicine are no longer to be used as growth promoters, and all new agents proposed as feed additives are scrutinised to ensure that their administration is unlikely to lead directly to resistance against antimicrobial agents used therapeutically. But the use of antimicrobial agents for treatment of infected farm animals is much harder to control. Furthermore, there is the possibility of genetic transfer to human and animal pathogens of resistance to antimicrobial agents permitted as food additives, being accompanied by resistance to antimicrobial agents used for treating people and animals. E. S. ANDERSON has repeatedly pointed out21,22 that when an organism has acquired resistance to several antimicrobial agents, and especially when the genes for these resistances are linked on one plasmid, exposure to any one of the agents will select for resistance to them all. The position today is unhappily reminiscent of that of the early 1960s, when epidemics of salmonellosis led to the appointment of the Swann Committee. Ten years after the committee’s report, resistant salmonellas in food animals are not even under control, much less eliminated. Is it sensible or even necessary to use chloramphenicol, and other agents which can save the lives of human beings, in the treatment of salmonellosis in calves and other food animals? To what extent are antibiotics, prescribed for treatment of infections in animals, being diverted, without veterinary consent, into use as feed additives for promoting growth?) Has everyone forgotten the lessons learned in previous outbreaks about the role of bad husbandry inl causing infection, and about how good rearing
tance
.
þ
_
-
Report of
21 22
bandry and Veterinary Medicine, H M Stationery Office, 1969. Anderson,E. S., Lewis M. J. Nature, 1965, 206, 579. Anderson, FS. New scientist, 1974 61, 750.
the
Joint Committee
on
the
use
of Antibiotics
Animal Hus
20
in
eliminate infection? And what has become of the proposed protein processing order,-, under which all protein-containing animal feed used in the U.K. would be subjected to heat-treatment sufficient to destroy salmonellas? This measure is long overdue. To be effective such an order would have to be accompanied by systematic eradication of salmonellas from existing stocks of animals and the premises in which they are housed. One final point. Those doctors who criticise their veterinary colleagues for the indiscriminate and inappropriate use of antimicrobial agents in animals, should pause awhile before casting their stones. We all need to think more critically before prescribing an antimicrobial agent, whether it be the latest mycin or an older but still valuable member of our antimicrobial reserve. A little more restraint in prescribing, and a few more controls in barn and field, could greatly lessen the rate at which our antimicrobial resources are being squandered.
practice
-
can
THE NEW GOVERNMENT
PERHAPS the new Conservative Government was elected because enough voters acted in the belief that only a change in leadership could realise Britain’s full economic potential and unite the people in a creative effort to dispel the total self-interest induced by inflation and fear of unemployment. Whatever the reasons, those who detected vagueness, inconsistency, and disruptiveness in Conservative arguments must now take heart from an air of hopefulness in the land-an emotion running counter to the woe cried by many who believe they have witnessed no more than another tilt in an impotent political seesaw. Despite fears that they were inviting the citizens to expect early and ample reward for votes, the Conservatives won a majority large enough to show that their case had indeed generated more hope than Mr Callaghan could evoke after the positive achievements of his administration had been shadowed by the winter’s troubles, but a majority small enough to counsel caution against swift action in sensitive matters like industrial relations and trade-union powers. The goodwill now on the surface (maybe the nation is elated by its own daring in choosing a woman as Prime Minister) must be deepened and sustained if reforms and changes of attitude are to be won by consultation and avoidance of conflict. For the National Health Service, with the report of the Royal Commission expected in a month or two, no sudden change is forecast. The N.H.S. sprang from an idealistic base which seemed secure in 1948 and yet has proved in the ’60s and ’70s to be terribly vulnerable to rising costs, the inflation-stoked demands of its employees, and the high expectations of a society which sees that medical care has much more to offer than it had in the ’40s. As the Conservative manifesto argued, more can be achieved for the same money by further improvements in N.H.S. housekeeping. But there is little to be gained and much to be lost by cutting the cost of the N.H.S. through new or higher financial barriers or bB encouraging private practice (at the inevitable expense of N.H.S. manpower resources). It is, in fact, the cen
